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SAR439459 (SAR'459), a "second‐generation" human anti‐transforming growth factor beta (TGFβ) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty‐eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness‐of‐fit plots and adequately described the observed data by a two‐compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment‐emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients. [ABSTRACT FROM AUTHOR]

Introduction: Targeting HRD with PARP inhibitors is now considered a standard treatment strategy in different tumor types. Whether HRD can be used as a tumor-agnostic predictive biomarker for PARP inhibition is not well established. Methods: A 43-year-old woman with no relevant past medical history or family history of cancer was diagnosed with metastatic uterine leiomyosarcoma with lung metastases in 2020. The patient started first line chemotherapy with doxorubicin achieving a partial response as best response and a duration of response of 5 months. Upon disease progression, the patient was initiated on second line pazopanib but required treatment discontinuation due to treatment-related heart failure with an ejection fraction of 40%. Patient was referred to the phase 1 clinical trials unit at Vail d Hebron University Hospital. Comprehensive genomic profiling was performed using a CLIA certified panel testing 447 genes. Molecular profiling showed a two-copy deletion of BRCA2. TMB of 4.562 mutations per megabase. Tumor was mismatch-repair proficient. Myriad myChoice HRD Plus showed BRCA2 deletion and a genomic instability score of 69 (threshold 42), supporting HRD. The patient was approached for an early phase clinical trial testing a treatment combination based on a PARP 1/2 inhibitor and temozolomide (TMZ). Results: Treatment was overall well tolerated with no grade 3 or 4 treatment-related toxicities. First CT scan 8 weeks from treatment initiation showed partial response (PR) with tumor shrinkage of the two target lesions located in the liver and mediastinum. Thirteen months after treatment initiation, this patient achieved a RECIST 1.1 complete response (CR) with disappearance of both target lesions, which has been sustained for over 24 months (Figure). Conclusion: The clinical case presented here, supports the potential clinical utility of HRD testing across tumor types. [ABSTRACT FROM AUTHOR]

Meningioma, the second most common primary tumour of the central nervous system, is classified into three different grades based on their characteristics. Each tumour grade includes different molecular subtype, growth potential, and thus, different prognosis. Grade I meningioma is the most common subtype with a benign course, in which systemic dissemination rarely occurs. We present the case of a 48- year- old male patient with a history of grade I meningioma who was referred 3 years after the initial diagnosis to our centre due to pelvic pain. Computed tomography (CT) images showed new pelvic bone lesions whose histopathological report was compatible with a grade I meningioma. Neither hormonal therapy concomitant with octreotide nor hydroxiurea treatments were effective. Very little is known about this entity’s prevalence and treatment when disseminated disease occurs. Thus, we think it is important to increase the positive and negative clinical experiences in this setting. [ABSTRACT FROM AUTHOR]

SAR439459 (SAR'459), a "second-generation" human anti-transforming growth factor beta (TGFβ) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty-eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness-of-fit plots and adequately described the observed data by a two-compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment-emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Tusamitamab ravtansine is an antibody-drug conjugate that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivers a cytotoxic maytansinoid payload. In a phase I dose-escalation study, the maximum tolerated dose (MTD) was 100 mg/m 2 every 2 weeks (Q2W). Here we report results for two alternative schedules., Experimental Design: Adults ages ≥18 years (range, 34-73) with locally advanced/metastatic solid tumors ( N = 43; colon/rectum, 29; stomach, 7; pancreas, 4; other, 3) expressing/likely to express CEACAM5 received intravenous tusamitamab ravtansine 120-170 mg/m 2 [loading dose (LD)], then 100 mg/m 2 Q2W (Q2W-LD, n = 28), or 120-190 mg/m 2 fixed dose [every 3 weeks (Q3W), n = 15]. The primary endpoint was dose-limiting toxicities (DLTs) during cycles 1-2 (Q2W-LD) and cycle 1 (Q3W)., Results: Reversible DLTs were observed in 2 of 9 patients (grade 2 keratopathy; grade 2 keratitis) with 170 mg/m 2 in Q2W-LD and in 2 of 3 patients (grade 2 keratopathy; grade 3 transaminase elevation) with 190 mg/m 2 in Q3W. Nineteen (67.9%) patients in Q2W-LD and 13 (86.7%) patients in Q3W experienced treatment-related adverse events (AE); 3 of 43 patients discontinued treatment because of AEs. The most common AEs were asthenia, gastrointestinal complaints, keratopathy, keratitis, and peripheral sensory neuropathy. In this small, heavily pretreated population, no confirmed responses were observed; however, stable disease occurred in 35.7% of patients in Q2W-LD and 40.0% of patients in Q3W., Conclusions: Tusamitamab ravtansine had a favorable safety profile with both alternative administration schedules; MTDs were 170 mg/m 2 (LD) followed by 100 mg/m 2 Q2W, and 170 mg/m 2 Q3W as a fixed dose. (NCT02187848)., Significance: The collective results of this phase I dose-escalation study will inform further studies of tusamitamab ravtansine in patients with solid tumors with CEACAM5 expression, including patients with non-small cell lung cancer., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation., Methods: This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II., Results: Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each)., Conclusions: Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)